RT Journal Article
SR Electronic
T1 Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 652
OP 659
DO 10.1136/annrheumdis-2014-206191
VO 75
IS 4
A1 Hirotaka Matsuo
A1 Ken Yamamoto
A1 Hirofumi Nakaoka
A1 Akiyoshi Nakayama
A1 Masayuki Sakiyama
A1 Toshinori Chiba
A1 Atsushi Takahashi
A1 Takahiro Nakamura
A1 Hiroshi Nakashima
A1 Yuzo Takada
A1 Inaho Danjoh
A1 Seiko Shimizu
A1 Junko Abe
A1 Yusuke Kawamura
A1 Sho Terashige
A1 Hiraku Ogata
A1 Seishiro Tatsukawa
A1 Guang Yin
A1 Rieko Okada
A1 Emi Morita
A1 Mariko Naito
A1 Atsumi Tokumasu
A1 Hiroyuki Onoue
A1 Keiichi Iwaya
A1 Toshimitsu Ito
A1 Tappei Takada
A1 Katsuhisa Inoue
A1 Yukio Kato
A1 Yukio Nakamura
A1 Yutaka Sakurai
A1 Hiroshi Suzuki
A1 Yoshikatsu Kanai
A1 Tatsuo Hosoya
A1 Nobuyuki Hamajima
A1 Ituro Inoue
A1 Michiaki Kubo
A1 Kimiyoshi Ichida
A1 Hiroshi Ooyama
A1 Toru Shimizu
A1 Nariyoshi Shinomiya
YR 2016
UL http://ard.bmj.com/content/75/4/652.abstract
AB Objective Gout, caused by hyperuricaemia, is a multifactorial disease. Although genome-wide association studies (GWASs) of gout have been reported, they included self-reported gout cases in which clinical information was insufficient. Therefore, the relationship between genetic variation and clinical subtypes of gout remains unclear. Here, we first performed a GWAS of clinically defined gout cases only.Methods A GWAS was conducted with 945 patients with clinically defined gout and 1213 controls in a Japanese male population, followed by replication study of 1048 clinically defined cases and 1334 controls.Results Five gout susceptibility loci were identified at the genome-wide significance level (p<5.0×10−8), which contained well-known urate transporter genes (ABCG2 and SLC2A9) and additional genes: rs1260326 (p=1.9×10−12; OR=1.36) of GCKR (a gene for glucose and lipid metabolism), rs2188380 (p=1.6×10−23; OR=1.75) of MYL2-CUX2 (genes associated with cholesterol and diabetes mellitus) and rs4073582 (p=6.4×10−9; OR=1.66) of CNIH-2 (a gene for regulation of glutamate signalling). The latter two are identified as novel gout loci. Furthermore, among the identified single-nucleotide polymorphisms (SNPs), we demonstrated that the SNPs of ABCG2 and SLC2A9 were differentially associated with types of gout and clinical parameters underlying specific subtypes (renal underexcretion type and renal overload type). The effect of the risk allele of each SNP on clinical parameters showed significant linear relationships with the ratio of the case–control ORs for two distinct types of gout (r=0.96 [p=4.8×10−4] for urate clearance and r=0.96 [p=5.0×10−4] for urinary urate excretion).Conclusions Our findings provide clues to better understand the pathogenesis of gout and will be useful for development of companion diagnostics.